The freeze drying process consists of three stages: prefreezing, primary drying, and secondary drying.
Prefreezing: Since freeze drying is a change in state from the solid phase to the gaseous phase, material to be freeze dried must first be adequately prefrozen. The method of prefreezing and the final temperature of the frozen product can affect the ability to successfully freeze dry the material.
Rapid cooling results in small ice crystals, useful in preserving structures to be examined microscopically, but resulting in a product that is more difficult to freeze dry. Slower cooling results in larger ice crystals and less restrictive channels in the matrix during the drying process.
Products freeze in two ways, depending on the makeup of the product. The majority of products that are subjected to freeze drying consist primarily of water, the solvent, and the materials dissolved or suspended in the water, the solute. Most samples that are to be freeze dried are eutectics which are a mixture of substances that freeze at lower temperatures than the surrounding water. When the aqueous suspension is cooled, changes occur in the solute concentrations of the product matrix. And as cooling proceeds, the water is separated from the solutes as it changes to ice, creating more concentrated areas of solute. These pockets of concentrated materials have a lower freezing temperature than the water. Although a product may appear to be frozen because of all the ice present, in actuality it is not completely frozen until all of the solute in the suspension is frozen. The mixture of various concentration of solutes with the solvent constitutes the eutectic of the suspension. Only when all of the eutectic mixture is frozen is the suspension properly frozen. This is called the eutectic temperature.
It is very important in freeze drying to prefreeze the product to below the eutectic temperature before beginning the freeze drying process. Small pockets of unfrozen material remaining in the product expand and compromise the structural stability of the freeze dried product.
The second type of frozen product is a suspension that undergoes glass formation during the freezing process. Instead of forming eutectics, the entire suspension becomes increasingly viscous as the temperature is lowered. Finally the product freezes at the glass transition point forming a vitreous solid. This type of product is extremely difficult to freeze dry.
Primary drying: Several factors can affect the ability to freeze dry a frozen suspension. While these factors can be discussed independently, it must be remembered that they interact in a dynamic system, and it is this delicate balance between these factors that results in a properly freeze dried product.
After prefreezing the product, conditions must be established in which ice can be removed from the frozen product via sublimation, resulting in a dry, structurally intact product. This requires very careful control of the two parameters, temperature and pressure, involved in the freeze drying system. The rate of sublimation of ice from a frozen product depends upon the difference in vapor pressure of the product compared to the vapor pressure of the ice collector. Molecules migrate from the higher pressure sample to a lower pressure area. Since vapor pressure is related to temperature, it is necessary that the product temperature is warmer than the cold trap (ice collector) temperature. It is extremely important that the temperature at which a product is freeze dried is balanced between the temperature that maintains the frozen integrity of the product and the temperature that maximizes the vapor pressure of the product. This balance is key to optimum drying. The typical phase diagram shown in Figure 1 illustrates this point. Most products are frozen well below their eutectic or glass transition point (Point A), and then the temperature is raised to just below this critical temperature (Point B) and they are subjected to a reduced pressure. At this point the freeze drying process is started.